8-chloropyrazolo-[1, 5-c]quinazoline derivatives and methods of preparing same



United States Patent 8 CHLOROPYRAZOLO-[1,5-c1QUINAZOLINE DE-gljiVAETllvES AND METHODS OF PREPARING Roger T. Wolfe, North Greenbush,and Alexander R. Surrey, Albany, N.Y., assignors to Sterling Drug Inc.,New York, N.Y., a corporation of Delaware N0 Drawing. Filed May 4, 1964,Ser. No. 364,782

15 Claims. (Cl. 260-2564) This invention relates to novel organicheterocyclic compounds and to methods and intermediates for theirpreparation.

One aspect of the invention relates to 8-chloro-5-R-5,6-dihydropyraz-olo[1,5-c]quinazolines having in free base form thestructural formula wherein R is a member of the group consisting of H,phenyl, pyridyl, thienyl, furyl, carboxy, and carbalkoxy.

When R is one of the aryl groups phenyl, pyridyl, thienyl or furyl, itcan be unsubstituted, or it can be substituted with up to threesubstituents. The said substituents can be the same or different and canbe located in any of the available ring positions relative to eachother. Examples of substituents which can be attached to the aryl groupsare lower-alkyl, lower-alkoxy, nitro, halo (i.e., chloro, bromo, iodoand fluoro), hydroxy, mercapto, loWer-alkylthio, di-(lower-alkyl)-amino,carboxy, lower-alkanesulfonyl, trifluor-omethyl, and the like.

When R is carbalkoxy, it is the group -COOR' where R is a straightorbranched-chain alkyl group of from one to about ten carbon atoms. Thuscarbalkoxy includes such groups as carbomethoxy, carbethoxy,carbopropoxy, carboisopropoxy, carbobutoxy, carbopentyloxy,carbo'hexyloxy, carboheptyloxy, car booctyloxy, carbononyloxy,carbodecyloxy, carbo-sec-but-oxy, and the like.

A further aspect of the invention relates to S-chloro-S-X(6H)pyrazolo[l,5-c]quinazolines having in free base form the generalformula wherein X is a member of the group consisting of O 3,313,815Patented Apr. 11, 1967 "ice pyrazolo[l,5-c]quinazolines having in freebase form the structural formula 10 III The benzo ring of the compoundsof :Formulas I, II, and III bears a chloro substituent in the8-position; Said chloro substituent can be replaced by othersubstituen'ts for the purposes of this invention. Moreover, thesubstituent is not limited to the 8-position, but can reside at any ofthe available positions of the benzo ring, i.e., 7, 8, 9 or 10. Examplesof substituents which can replace the 8-chlorosubstituent illustrated inFormula I include nitro, lower-alkanesulfonyl, bromo, iodo, fluoro,trifiuoromethyl, lower-alkoxy, lower-alkylthio, di-(loweralkyl)amino andlower alkanoylamino.

The compounds of Formula I are prepared by reacting 3 (Z-amino 4chlorophenyDpyraz-ole having the formula with an aldehyde, RCHO, forexample formaldehyde (R=H), benzaldehyde (R=phenyl), 2-, 3-, or4-pyridine aldehyde (R=pyridyl), 2- or 3-thiophene aldehyde (R=thienyl),2- or 3-furaldehyde (R=furyl) and glyoxylic acid (R=carboxy). Thepreparation requires only that the reactants be heated in an inertsolvent at about l50 C. for a short time. It is convenient, however, toreflux a solution of the reactants in a waterimmiscible solvent under awater trap so that the progress of the reaction can be observedvisually; that is, completion of the reaction is indicated when thetheoretical quantity of water, the byproduct of the reaction, hascollected in the water trap. Suitable solvents for the reaction formazeotropic mixtures with water and therefore remove the water as it isformed in the reaction. Examples of such solvents include benzene,toluene, O xylene, dichloromethane, methyl isobutyl ketone, and thelike. The time needed for completion of the reaction depends upon theboiling point of the particular solvent used, but the reaction time isordinarily from one to two hours.

When the aldehydic reactant is glyoxylic acid, the reaction can 'becarried out either in an inert solvent to yield aS-carboxy-S,6-dihydropyrazolo 1,5 -c] quinazoline or in an alkanol, toyield the corresponding ester, i.e., a S-carbalkoxy 5,6dihydropyrazolo[l,5-c]quinazoline. Preferred alkanols for the latterreaction boil below 200 C. and include methanol, ethanol, propanol,isopropyl alcohol, butanol, sec-butyl alcohol, tert-butyl alcohol,isobutyl alcohol, pentanol, hexanol, heptanol, octanol, and the like,and lead to the corresponding methyl, ethyl, propyl, isopropyl, butyl,sec-butyl, tert-butyl, isobutyl,

pentyl, hexyl, heptyl, octyl, and the like esters.

The compounds of Formula II are prepared byreacting3-(2-amino-4-chlorophenyl)pyrazole (Formula IV) with phosgene (whereX=O), or thiophosgene or carbon 0 disulfide (Where X=S). The reaction isconducted in an inert solvent in the presence of a strong base. Whenphosgene or thiophosgene is a reactant, the base employcd neutralizesthe hydrogen chloride formed in the reaction. When carbon disulfide isthe reactant, only a small quantity of a base is used, and hydrogensulfide is evolved from the reaction mixture. Suitable strong bases forthis reaction include alkali, alkaline earth, and quaternary ammoniumhydroxides.

The compound of Formula III is prepared by reacting3-(2-amino-4-chlorophenyl)pyrazole (Formula IV) with an orthoformicester, for example ethyl orthoformate. Although the reaction can becarried out in an enert solvent it is convenient and preferred to employan excess of the ortho ester as a solvent. Thus when a solution of3-(2-amino-4-chlorophenyl) yrazole dissolved in excess ethylorthoforrnate is refluxed for several hours,8-chloropyrazole[1,5-c]quinazoline is obtained.

The free bases of Formulas I, II and III react with organic andinorganic acids to form acid-addition salts which are the fullequivalents of the free base forms. Where the newpyrazolo[l,5-c]quinazolines contain several basic centers, they can formacid-addition salt forms with one or several molecular equivalents ofthe inorganic or organic acid.

The acid-addition salt forms of the basic amines and amides of theinvention are conveniently obtained by interacting the free bases withthe appropriate equivalent of an organic or inorganic acid. The acidmoieties or anions in these salt forms are in themselves neither novelnor critical and therefore can be any anion of acidlike substancecapable of salt formation with the free base form of the compound.

The compounds of Formulas I, II and III have been tested by standardpharmacological and bacteriological testing procedures and found to havehypotensive, psychomotor depressant and bacteriostatic activities.

The structures of the compounds of the invention were determined byinfra-red spectral analysis, 'by their chemical properties, e.g., theformation of derivatives, and by the correspondence of calculated andfound values of elemental analyses of representative samples.

The examples which follow illustrate the invention Without limiting thelatter thereto.

Example 1.3-(2-amino-4-clzlorophenyl)pyrazole A mixture of 150 g. (0.76mol) of 4,7-dichloroquinoline and 450 g. (9 mols) of 100% hydrazinehydrate was placed in an autoclave and heated at 150 with agitation forhours. The mixture was allowed to cool and was poured into a largeexcess of ice water. The precipitate, consisting of crude3-(2-amino-4-chlorophenyl)pyrazole was collected and was recrystallizedfrom 10% aqueous ethanol. Recrystallized again from benzene, the pure3-(2-amino-4-chlorophenyl)pyrazole, consisting of ten needles, melted at115.81l7.2 C. (corr.).

Example 2.-3- (2-amin0-6-chl0r0phenyl pyrazole Following the proceduregiven in Example 1, 40 4,5-dichloroquinoline was caused to react with120 of 100% hydrazine hydrate in an autoclave. Recrystallized fromisopropyl alcohol the pure 3-(2-amino-6-chlorophenyl)pyrazole thusobtained melted at 1.05.4107.4 C. (corr.).

The hydrochloride acid-addition salt form melted at 232236 C.

When 8-chloro 5 (4-chlorophenyl)-5,6-dihydropyrazolo[1,5-c]quinazolinewas caused to react with a slight excess of nitrous acid (sodium nitritein glacial acetic acid) there was obtained 8-chloro-5-(4-chlorophenyl)-5,6-dihydro-6-nitrosopyrazolo[1,5-c]quinazoline which, afterrecrystallization from isopropyl alcohol, melted with decomposition at131.8-137.4 C. (corr.).

When S-chloro 5 (4-chlorophenyl)-5,6-dihydropyrazolo[1,5-c]quinazolinewas refluxed in excess acetyl chloride there was obtained6-acetyl-8-chloro-5-(4-chlorophenyl)-5,6-dihydropyrazolo[1,5-c]qu,inazolinewhich, after recrystallization from ethyl acetate, melted at 231.6 233.8C.

Example 4.-8 chloro 5 (2 hydroxyphenyl) 5,6-dihydropyrazolo[1,5-c1quinazoiine Following the procedure given inExample 3, 19.4 g. (0.1 mol) of 3-(2-amino-4-chlorophenyl)pyrazole wascaused to react with 12.2 g. (0.1 mol) of salicylaldehyde dissolved in150 ml. of methyl isobutyl ketone under a water separator.Recrystallized from isopropyl alcohol the 8 chloro 5 (2 hydroxyphenyl)5,6 dihydropyrazololl,5-c]quinazoline thus prepared melted at 213.2221.8 C. (corr.).

Example 5.8 chloro 5 (3 pyria'yl) 5,6 dihydropyraz0l0[I,5-c]quinazolineFollowing the procedure given in Example 3, 3-(2-amino-4-chlorophenyl)pyrazole was caused to react with one molecularequivalent of 3-pyridine carboxaldehyde in methyl isobutyl ketone.Recrystallized from ethylene dichloride the8-chloro-5-(3-pyridy1)-5,6-dihydropyrazolo [l,5-c]quinazoline thusprepared melted at 175.0176.6 C. (corr.).

Example 6.8 chloro 5,6 dihydropyrazolo[1,5-0] quinazoiine-S-carboxylicacid Following the procedure given in Example 3, 3-(2-amino-4-chlorophenyl)pyrazole was refluxed with one molecular equivalentof glyoxylic acid in methyl isobutyl ketone. The product,8-chloro-5,6-dihydropyrazolo[1,5- c]quinazoline-S-carboxylic acid,crystallized from the reaction mixture and melted with decomposition at188.6- l89.6 C. (corr.).

Example 7.5 carboburoxy 8 chloro 5,6 dihydropyrazolo [1 ,5 -c]quinazoline Example 8.8-chl0r0pyraz0l0[1,5-c1quinazoline Following theprocedure given in Example 3, 9.7 g. of3-(2-amino-4chlorophenyl)pyrazole and 10 g. of ethyl orthoformate in ml.of methyl isobutyl ketone were refluxed for 6 hours. When the resultingsolution was cooled, the produce crystallized. Recrystallized fromisopropyl alcohol, the 8-chloropyrazolo[1,5-c]quinazoline thus preparedmelted at l6l.2l62.8 C. (corr.).

Example 9.8-chl0r0pyrazol0 [1,5-c] quinaz0lin-5(6H) one3-(2-amino-4-chlorophenyl)pyrazole (9.7 g.; 0.05 mol) was dissolved inml. of ethylene dichloride and to the solution was added 100 ml. ofwater. The resulting mixture was stirred thoroughly while phosgene gaswas slowly introduced. The mixture was maintained basic by the periodicaddition of 10% sodium hydroxide solution. During the course of thereaction, a light colored precipitate formed. After about 1 hour, theethylene dichloride layer appeared to contain no more, startingmaterial, and the aqueous layer remained basic. The mixture was flushedthoroughly with nitrogen to remove excess phosgene, and the product wascollected. Recrystallized from dimethylformamide, the8-chloropyrazolo[l,5-c]quinazolin-S (6H)-one thus prepared melted above300 C.

Example 10.8-chl0r0pyrz'zz0!o[1,5-c] quinazolin-S (6H) thione A solutioncontaining 10 g. of 3-(2-amino-4-chlorophenyl)pyrazole, 10 g. of carbondisulfide and a catalytic quantity of trimethylbenzyl ammonium hydroxidein 100 ml. of benzene was refluxed for 7 hours, during which time thecrude product precipitated. After the solution had cooled theprecipitate was collected and recrystallized from 10% dimethylformamidein isopropyl alcohol. The resulting pure 8-chloropyrazolo 1,5-c]quinazolin-S (6H) thione, consisting of white crystals, melted at 327-3285 C. Example 11.8-chZora-5,6-dihydr0pyrazol0[1,5-c] quinazolineFollowing the procedure given in Example 3, 9.7 g. (0.05 mol) of3-(2-arnino-4-chlorophenyl)pyrazole was refluxed with 3.0 g. (0.1 mol)of paraformaldehyde and two drops of concentrated hydrochloric acid in150 ml. of benzene. The theoretical quantity of water was collected inthe water separator in 1 hour. The solvent was removed under reducedpressure, yielding crude 8-chloro- 5,6-dihydropyrazolo[l,5-c]quinazolineas a brown gum. The hydrochloride salt form, which was prepared byadding to the gum an excess of hydrogen chloride in ether, consisted ofa nearly white powder which was very deliquescent and was not purified.

Following the manipulative procedure given in Example 1, the followingsubstituted 3-(2-aminophenyl)pyrazole compounds are prepared using theindicated quinoline compound in place of 4,7-dichloroquinoline:

3-(2-amino-4-bromophenyl)pyrazole, from 7-bromo-4- chloroquinoline.

3-(2-arnino-5-dimethylarninophenyl)pyrazole, from 4-chlor-6-dimethylaminoquinoline.

3-(2-amino-S-methoxyphenyl)pyrazole, from 4-chloro- 6-methoxyquinoline.

3-(2amino-4-hexyloxyphenyl)pyrazole, from 4-chloro- 7-hexyloxyquinoline.

3-(2-amino-3-methoxyphenyl)pyrazole, from 4-chloro- 8-methoxyquinoline.

3-(2-amino-5-nitrophenyl)pyrazole, from 4-ch1oro-6- nitroquinoline.

3-(S-acetamido-2-aminophenyl)pyrazole, from 6-acetamido-4chloroquinoline.

3-(2-amino-5-fiuorophenyl)pyrazole, from 4-chloro-6- fiuoroquinoline.

3-(2-amino-4-iodophenyl)pyrazole, from 4-chloro-7- iodoquinoline.

3-(2-amino-3-nitrophenyl)pyrazole, from 4-chloro-8- nitroquinoline.

3-(2-amino-4-trifiuoromethylphenyl)pyrazole, from 4-chloro-7-trifluoromethylquinoline.

3 (2 amino methylthiophenyl)pyrazole, from4-chloro--methylthioquinoline.

Following the manipulative procedure given in Example 3, the followingcompounds are prepared from the indicated pyrazole compound andbenzaldehyde:

8-bromo-5-phenyl-5,6-dihydropyrazolo 1,5-c] quinazoline, from3-(2-amino-4-bromophenyl)pyrazole.

9-dimethylamino-S-phenyl-S ,6-dihydropyrazolo[ 1,5 -c] quinazoline, from3-(Z-amino-S-dimethylaminophenyl) pyrazole.

6 9-methoxy-5-phenyl-5,6-dihydropyrazolo[1,5-c]quinazoline, from3-(Z-amino-S-methoxyphenyl)pyrazole.8-hexyloxy-5-phenyl-5,6-dihydropyrazolo[1,5-c]quinazoline, from3-(2-amino-4-hexyloxyphenyl) pyrazole.7-methoxy-5-phenyl-5,6-dihydropyrazolo 1,5 -c] quinazoline, from3-(2-amino-3-methoxyphenyl)pyrazole. 9-nitro-5-phenyl-5,6-dihydropyrazolo[ 1,5-c] quin azoline,

from 3-(Z-amino-S-nitrophenyl) pyrazole.9-acetamido-S-phenyl-5,6-dihydropyrazolo[ 1,5-c] quinazoline, from3-(5-acetamido-Z-aminophenyl)pyrazole.9-fiuoro-5-phenyl-5,6-dihydropyrazolo 1,5-c] quinazoline,

from 3 Z-amino-S-fiuorophenyl pyrazole.8-iodo-5-phenyl-5,6-dihydropyrazolo 1,5-c] quinazoline,

from 3 2-amino-5-iodophenyl pyrazole.7-nitro-5-phenyl-5,6-dihydropyrazolo 1,5-c] quinazoline,

from 3 2-arnino-3 -nitrophenyl pyrazole.5-phenyl-8-trifluoromethyl-5,6-dihydropyrazolo[1,5-c]

quinazoline, from 3-(2-amino-4-trifiuoromethylphenyl) pyrazole.9-methylthio-5-phenyl-5 ,6-dihydropyrazolo 1,5 -c] quinazoline, from3-(Z-amino-5methylthiophenyl)pyrazole.

Following the manipulative procedure given in Example 3, the following8-chloro-5,6-dihydropyrazolo[1,5- c]quinazolines are prepared using theindicated aldehyde in place of 4-chlorobenzaldehyde:

8-chloro-5-(4-rnethoxyphenyl)-5,6-dihydropyrazolo [1,5-c1quinazoline,from anisaldehyde. 8-chloro-5- 4-dirnethylaminophenyl)5,6-dihydropyrazolo [l,5-c]quinazoline, from4-dimethylaminobenzaldehyde. 8-chloro-5-phenyl-5 ,6-dihydropyrazolo1,5-c] quinazoline, from benzaldehyde.8-chloro-5-(3-nitrophenyl)-5,6-dihydropyrazolo[1,5-c]

quinazoline, from 3-nitrobenzaldehyde.8-chloro-5-(3,4-dihydroxyphenyl)-5,6-dihydropyrazolo [1,5-c]quinazoline,from 3,4-dihydroxybenzaldehyde. 8-chloro-5- (4-diethylaminophenyl)-5,6-dihydropyrazolo [1,5-c] quinazoline, from4-dimethylaminober'1zaldehyde.8-chloro-5-(3-ethoxy-4-hydroxyphenyl)-5,6-dihydropyrazolo 1,5-c]quinazoline, from 4-dimethylaminobenzaldehyde. 8-chloro-5-(3-ethoxy-4-hydroxyphenyl)-5,6-dihydropyrazolo[1,5-c]quinazoline, from3-ethoxy-4-hydroxybenz aldehyde.8-chloro-5-(S-chloro-Z-hydroxyphenyl)-5,6-dihydropyrazolo[1,5-c1quinazoline, from S-chlorosalicylaldehyde.8-chloro-5-(2,4-dichlorophenyl)-5,6-dihydropyrazolo[1,5-

c] quinazoline, from 2,4-dichlorobenzaldehyde. 8-chloro-5-(S-brorno-Z-hydroxyphenyl) -5,6-dihydropyrazolo 1,5-c] quinazoline, fromS-brornosalicylaldehyde. 8-chloro-5- Z-furyl) -5,6-dihydropyrazolo1,5-c] quinazoline, from 2-furaldehyde. 8-chloro-5- 2,4,6-trinitrophenyl-5,6'dihydropyrazolo 1 5-c]quinazoline, from 2,4,6-trinitrobenzaldehyde.8-chloro-5-(3,4,5-trimethoxyphenyl)-5,6-dihydropyrazolo[ 1,5-c]quinazoline, from 3,4,5-trimethoxybenzaldehyde.8-chloro-5-(2-thienyl)-5,6-dihydropyrazolo[1,5-c]quinazoline, from2-thiophenecarboxaldehyde. 8-chloro-5(5-nitrofuryl)-5,6-dihydropyrazolo[1,5-c]

quinazoline, from S-nitrofurfural. 8-ch1oro-5-(4-pyridyl)-5,6-dihydropyrazolo 1,5-c] quinazoline, from 4-pyridinecarboxaldehyde.8-chloro-5-(4-tolyl)-5,6-dihydropyrazolo[1,5-c1quinazoline, from4-tolualdehyde. 8-chloro-5-(2,3,6-trimethylphenyl)-5,6-dihydropyraz0lo[1,5 -c] quinazoline, from 2,3,6-trimethylbenzaldehyde.8-chloro-5-(4-se-c-butylphenyl)-5,6-dihydropyrazolo[1,5-

c]quinazo1ine, from 4-sec-butylbenzaldehyde.8-chloro-5-(S-methylfuryl)-5,6-dihydropyrazolo[1,5-c]

quinazoline, from S-methylfurfural. 8-chloro-5-(3-methyl-2-thienyl)-5,6-dil1ydropyrazolo [1,

'2 5-c1quinazo1ine, from 3-methy1-2-thiophenecarboxaldehyde.8-chloro-5-(3-thieny1)-5,6-dihydropyrazo1o[1,5-c1quinazoline, from3-thiophenecarboxaldehyde. 8-ch1oro-5-(Z-fiuorophenyl-5,6-dihydropyrazo1o 1,5-c]

quinazoline, from Z-fluorobenzaldehyde.8-ch1oro-S-(4-iodophenyl)-5,6-dihydropyrazo1o[1,5-c]

quinazoiine, from 4-iodobenza1dehyde.8-ch1oro-5-(4-trifluoromethy1pheny1)-5,6-dihydropyrazolo[1,5-c1quinazo1ine,from 4-trifiuoromethy1benza1- dehyde.8-ch1oro-5-(Z-mercaptophenyl)-5,6-dihydr0pyrazo1o[1,5-

c]quinazo1ine, from 2-mercaptobenza1dehyde.S-chloro-S-(2-methylmercaptophenyl)-5,6-dihydropyrazo1o[1,5-c]quinazo1ine,from Z-methylmercaptobenzaldehyde. 8-ch1oro-5- (4-methanesulfony1pheny1)-5 ,6-dihydropyrazolo[1,5-c1quinazo1ine, from4-methanesu1fony1benzaldehyde.8-ch1oro-5-(4-carboxypheny1)-5,6-dihydropyrazo1o[1,5-c]

quinazoline, from terephthalaldehydic acid.

We claim: 1. A compound of the formuia wherein R is a member of thegroup consisting of H, phenyl, pyridyl, thienyl, furyl, carboxy andCOOR, wherein R is alkyl of from one to ten carbon atoms.

2. 8 chioro 5 (4 chlorophenyl)-5,6-dihydropyrazo1o[1,5c]quinazo1ine.

3. 8 chloro 5 (2 hydroxyphenyl) 5,6 dihydropyrazo1o[1,5-c]quinazoline.

4. 8 chloro 5 (3 pyridyl) 5,6 dihydropyrazo1o[1,5-c]quinazo1ine.

5. 8 chloro 5,6 dihydropyrazolo[1,5-c]quinazoline-S-carboxylic acid.

6. 5 carbobutoxy 8 chloro-S,6 dihydropyrazolo [1,5-c1-quinazo1ine.

7. A compound of the formula 14. 8chloro-S-(4-ch1oropheny1)-5,6-dihydro-6-acetylpyrazo1o[1,5-c]quinazo1ine.

15. 8 chloro-S-(4-ch1oropheny1)-5,6-dihydro-6-nitrosopyrazo1o[ 1,5 -c]quinazoline.

References Cited by the Examiner UNITED STATES PATENTS 12/1960 Taylor eta1. 260256.4

OTHER REFERENCES De Stevens et a1.: Angew. Chem, vol. 74, p. 249 (1962).

De Stevens et a1.: Jour. Org. Chem, vol. 28, pp. 1336 1339 (May 1963).

ALEX MAZEL, Primary Examiner.

NICHOLAS S. RIZZO, HENRY R. JILES, Examiners.

MARY U. OBRIEN, Assistant Examiner.

UNITED STATES PATENT ()FFICE CERTIFICATE OF CORRECTKON Patent No. 3 ,313,8l5 April ll 1967 Roger T Wolfe et al.

5 in the above numbered patthat error appear nt should read as It ishereby certified d that the said Letters Pate ent requiring correctionan corrected below.

column 4, line Column 3, line 52, for "ten" read tan 67 for "produce"read product column 6, lines 41 to 43,

-4-hydroxyphenyl) 5 ,6-dihydrostrike out "8-chloro-5-(3-ethoxy pyrazolo[l ,5c]quinazoline from 4-dimethylaminobenzaldehyde Signed and sealedthis 22nd day of October 1968.

(SEAL) Attest:

EDWARD J. BRENNER Edward M. Fletcher, Jr.

Commissioner of Patents Attesting Officer

1. A COMPOUND OF THE FORMULA